Pyruvate dehydrogenase complex deficiencies (PDCD) are a major class of mitochondrial diseases, limiting oxidation of carbohydrate for energy production, which is especially important in the brain. PDCD is the second most common entry within the NAMDC Registry among registry participants with multiple mitochondrial enzyme defects. The best predictor of survival and cognitive outcome in those affected with PDCD appears to be the age of onset, with neonatal presentations typically associated with early death, and childhood onset cases associated with better survival and with normal or mild to severe cognitive disability. The mean and median ages of diagnosis of PDCD are about 31 and 12 months, respectively. We have sub-classified PDC deficient subjects into three different groups with important clinical consequences. Use of ketogenic diets is currently the main therapeutic intervention in a specific subclass of PDCD, but can be ineffective and/or lethal in subjects from the other subclasses. The proposed Advanced Genetic Study and Pilot Newborn Screening for PDC deficiency is in part a continuation of the work we have accomplished in our previous Natural History and Advanced Genetic Study of PDC deficiencies, where we have a) identified novel and known genes associated with pyruvate metabolism, b) have integrated natural history and molecular data with the NAMDC Registry and other databases, c) have sub-classified PDCD subjects into three groups - primary specific- primary generalized- and secondary-PDCD, and d) noted that patients diagnosed primary-specific PDCD would be the ones who would benefit most from initiation of a ketogenic diet. Our Aim #1 is to continue identifying novel genetic etiologies for PDCD using established advanced genetic analysis technologies in conjunction with functional confirmation when needed, which would enable better understanding of the pathophysiology of this disorder for future controlled clinical therapeutic intervention trials. Our Aim #2 is to pilot for the first time a newborn screening (NBS) protocol using biomarkers and specific molecular tests with the goal of diagnosing newborns with primary-specific PDCD for early intervention with ketogenic diet for better long-term health and cognitive outcomes. This pilot NBS PDC protocol is an Ohio-wide endeavor that includes two other NAMDC sites, which together constitute about 20% of all recruits with mitochondrial disorders in the NAMDC Registry.